Parkinson's disease is one of neurodegenerative disorders found in adults and elderly people. Parkinson's disease generally displays impaired motor functions, and one of the pathologic changes observed in Parkinson's disease is the degeneration or disappearance of dopamine neurons in the substantial nigra. Selective reduction in the dopamine level of a midbrain-basal ganglion system caused by this pathologic change can be suppressed by orally administered L-dopa, a dopamine precursor. Improvement in the symptoms is seen by this administration. Thus, L-dopa and dopamine receptor agonists are used as therapeutic drugs for Parkinson's disease. However, the administration of the dopamine precursor serves as merely a symptomatic therapy. The symptoms gradually progress, and the efficacy of these drugs declines. Therefore, in the end, patients with Parkinson's disease die in many cases.
Moreover, one of the pathological characteristics of Parkinson's disease is the appearance of Lewy bodies. Lewy body is a specific inclusion body that intracellularly appears in remaining neurons in the substantial nigra, locus coeruleus nucleus, vagus nerve nucleus, and so on. Furthermore, dementia with Lewy bodies (DLB) is also known as a disease in which Lewy bodies appear in the cerebral cortex, in addition to in the affected part of the brain stem.
While most cases of Parkinson's disease are sporadic, there exists a family line with autosomal dominant inheritance on rare occasions. From linkage analysis on family lines with familial Parkinson's disease, an α-synuclein gene located on the long arm of chromosome 4 was identified as a causative gene of Parkinson's disease, and missense mutations (A53T and A30P) in the gene were also confirmed (Polymeropoulos MH, et al., Science 1997 Jun. 27; 276 (5321): 2045-7; and Kruger R, et al., Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998 Feb; 18 (2): 106-8). Subsequent biochemical studies and immunohistological studies using anti-α-synuclein antibodies have revealed that Lewy bodies in sporadic Parkinson's disease and DLB are the result of accumulation of α-synuclein, and have shown the importance of accumulation of α-synuclein as a cause of Parkinson's disease.
Although transgenic animals that overexpress wild-type or variant α-synuclein have previously been reported as model mice of Parkinson's disease (International Publications WO 01/60794 and WO 98/59050, etc.), no previous report has described a transgenic animal whose intracerebral dopamine level is significantly decreased immediately after birth. Moreover, there has been no report about a transgenic animal in which the degeneration or disappearance of dopamine neurons in the substantial nigra, particularly the pathological feature of Parkinson's disease, that is, the degeneration or disappearance of dopamine neurons in the substantial nigra pars compacta is observed, while no change in the ventral tegmental area is observed.